Aldosterone inhibits the fetal program and increases hypertrophy in the heart of hypertensive mice
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Aldosterone inhibits the fetal program and increases hypertrophy in the heart of hypertensive mice. / Azibani, Feriel; Devaux, Yvan; Coutance, Guillaume; Schlossarek, Saskia; Polidano, Evelyne; Fazal, Loubina; Merval, Regine; Carrier, Lucie; Solal, Alain Cohen; Chatziantoniou, Christos; Launay, Jean-Marie; Samuel, Jane-Lise; Delcayre, Claude.
in: PLOS ONE, Jahrgang 7, Nr. 5, 5, 2012, S. e38197.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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TY - JOUR
T1 - Aldosterone inhibits the fetal program and increases hypertrophy in the heart of hypertensive mice
AU - Azibani, Feriel
AU - Devaux, Yvan
AU - Coutance, Guillaume
AU - Schlossarek, Saskia
AU - Polidano, Evelyne
AU - Fazal, Loubina
AU - Merval, Regine
AU - Carrier, Lucie
AU - Solal, Alain Cohen
AU - Chatziantoniou, Christos
AU - Launay, Jean-Marie
AU - Samuel, Jane-Lise
AU - Delcayre, Claude
PY - 2012
Y1 - 2012
N2 - BACKGROUND: Arterial hypertension (AH) induces cardiac hypertrophy and reactivation of "fetal" gene expression. In rodent heart, alpha-Myosin Heavy Chain (MyHC) and its micro-RNA miR-208a regulate the expression of beta-MyHC and of its intronic miR-208b. However, the role of aldosterone in these processes remains unclear.METHODOLOGY/PRINCIPAL FINDINGS: RT-PCR and western-blot were used to investigate the genes modulated by arterial hypertension and cardiac hyperaldosteronism. We developed a model of double-transgenic mice (AS-Ren) with cardiac hyperaldosteronism (AS mice) and systemic hypertension (Ren). AS-Ren mice had increased (x2) angiotensin II in plasma and increased (x2) aldosterone in heart. Ren and AS-Ren mice had a robust and similar hypertension (+70%) versus their controls. Anatomical data and echocardiography showed a worsening of cardiac hypertrophy (+41%) in AS-Ren mice (P<0.05 vs Ren). The increase of ANP (x 2.5; P<0.01) mRNA observed in Ren mice was blunted in AS-Ren mice. This non-induction of antitrophic natriuretic peptides may be involved in the higher trophic cardiac response in AS-Ren mice, as indicated by the markedly reduced cardiac hypertrophy in ANP-infused AS-Ren mice for one month. Besides, the AH-induced increase of ßMyHC and its intronic miRNA-208b was prevented in AS-Ren. The inhibition of miR 208a (-75%, p<0.001) in AS-Ren mice compared to AS was associated with increased Sox 6 mRNA (x 1.34; p<0.05), an inhibitor of ßMyHC transcription. Eplerenone prevented all aldosterone-dependent effects.CONCLUSIONS/SIGNIFICANCE: Our results indicate that increased aldosterone in heart inhibits the induction of atrial natriuretic peptide expression, via the mineralocorticoid receptor. This worsens cardiac hypertrophy without changing blood pressure. Moreover, this work reveals an original aldosterone-dependent inhibition of miR-208a in hypertension, resulting in the inhibition of β-myosin heavy chain expression through the induction of its transcriptional repressor Sox6. Thus, aldosterone inhibits the fetal program and increases cardiac hypertrophy in hypertensive mice.
AB - BACKGROUND: Arterial hypertension (AH) induces cardiac hypertrophy and reactivation of "fetal" gene expression. In rodent heart, alpha-Myosin Heavy Chain (MyHC) and its micro-RNA miR-208a regulate the expression of beta-MyHC and of its intronic miR-208b. However, the role of aldosterone in these processes remains unclear.METHODOLOGY/PRINCIPAL FINDINGS: RT-PCR and western-blot were used to investigate the genes modulated by arterial hypertension and cardiac hyperaldosteronism. We developed a model of double-transgenic mice (AS-Ren) with cardiac hyperaldosteronism (AS mice) and systemic hypertension (Ren). AS-Ren mice had increased (x2) angiotensin II in plasma and increased (x2) aldosterone in heart. Ren and AS-Ren mice had a robust and similar hypertension (+70%) versus their controls. Anatomical data and echocardiography showed a worsening of cardiac hypertrophy (+41%) in AS-Ren mice (P<0.05 vs Ren). The increase of ANP (x 2.5; P<0.01) mRNA observed in Ren mice was blunted in AS-Ren mice. This non-induction of antitrophic natriuretic peptides may be involved in the higher trophic cardiac response in AS-Ren mice, as indicated by the markedly reduced cardiac hypertrophy in ANP-infused AS-Ren mice for one month. Besides, the AH-induced increase of ßMyHC and its intronic miRNA-208b was prevented in AS-Ren. The inhibition of miR 208a (-75%, p<0.001) in AS-Ren mice compared to AS was associated with increased Sox 6 mRNA (x 1.34; p<0.05), an inhibitor of ßMyHC transcription. Eplerenone prevented all aldosterone-dependent effects.CONCLUSIONS/SIGNIFICANCE: Our results indicate that increased aldosterone in heart inhibits the induction of atrial natriuretic peptide expression, via the mineralocorticoid receptor. This worsens cardiac hypertrophy without changing blood pressure. Moreover, this work reveals an original aldosterone-dependent inhibition of miR-208a in hypertension, resulting in the inhibition of β-myosin heavy chain expression through the induction of its transcriptional repressor Sox6. Thus, aldosterone inhibits the fetal program and increases cardiac hypertrophy in hypertensive mice.
KW - Animals
KW - Male
KW - Female
KW - Mice
KW - Mice, Transgenic
KW - Gene Expression Regulation/drug effects
KW - Signal Transduction/drug effects
KW - Phosphoproteins/metabolism
KW - Aldosterone/metabolism/pharmacology/therapeutic use
KW - Cardiomegaly/complications/drug therapy/metabolism/pathology
KW - Cyclic AMP Response Element-Binding Protein/metabolism
KW - Fetus/drug effects/metabolism/pathology
KW - Hyperaldosteronism/complications
KW - Hypertension/complications
KW - MicroRNAs/genetics
KW - Myosin Heavy Chains/genetics/metabolism
KW - Natriuretic Peptides/genetics/metabolism
KW - Animals
KW - Male
KW - Female
KW - Mice
KW - Mice, Transgenic
KW - Gene Expression Regulation/drug effects
KW - Signal Transduction/drug effects
KW - Phosphoproteins/metabolism
KW - Aldosterone/metabolism/pharmacology/therapeutic use
KW - Cardiomegaly/complications/drug therapy/metabolism/pathology
KW - Cyclic AMP Response Element-Binding Protein/metabolism
KW - Fetus/drug effects/metabolism/pathology
KW - Hyperaldosteronism/complications
KW - Hypertension/complications
KW - MicroRNAs/genetics
KW - Myosin Heavy Chains/genetics/metabolism
KW - Natriuretic Peptides/genetics/metabolism
U2 - 10.1371/journal.pone.0038197
DO - 10.1371/journal.pone.0038197
M3 - SCORING: Journal article
C2 - 22666483
VL - 7
SP - e38197
JO - PLOS ONE
JF - PLOS ONE
SN - 1932-6203
IS - 5
M1 - 5
ER -
